tbuckley/cabot-search huggingface dataset:
Biomedical Imaging in Experimental Models of Cardiovascular Disease
Authors: David E. Sosnovik, Marielle Scherrer-Crosbie
Journal: Circulation Research (2022)

Major advances in biomedical imaging have occurred over the last 2 decades and now allow many physiological, cellular, and molecular processes to be imaged noninvasively in small animal models of cardiovascular disease. Many of these techniques can be also used in humans, providing pathophysiological context and helping to define the clinical relevance of the model. Ultrasound remains the most widely used approach, and dedicated high-frequency systems can obtain extremely detailed images in mice. Likewise, dedicated small animal tomographic systems have been developed for magnetic resonance, positron emission tomography, fluorescence imaging, and computed tomography in mice. In this article, we review the use of ultrasound and positron emission tomography in small animal models, as well as emerging contrast mechanisms in magnetic resonance such as diffusion tensor imaging, hyperpolarized magnetic resonance, chemical exchange saturation transfer imaging, magnetic resonance elastography and strain, arterial spin labeling, and molecular imaging.
TBIO-02. Mapping the origins of pediatric brain tumors to cell type lineages in the developing cerebellum.
Authors: Konstantin Okonechnikov, Piyush Joshi, Mari Sepp, Kevin Leiss, Ioannis Sarropoulos, David T W Jones, Marcel Kool, Natalie Jäger, Lena M Kutscher, Henrik Kaessmann, Stefan M Pfister
Journal: Neuro-Oncology (2022)

Abstract Understanding the cellular origins of cerebellar tumors at single cell resolution may help identify novel therapeutic vulnerabilities to overcome current impediments in pediatric neuro-oncology. One approach to answer this important question involves the mapping of tumor profiles onto normal embryonal central nervous system development. Previous attempts in this regard focused on integrating human tumor data with developing mouse cerebellum atlases, however, these approaches were inherently limited due to species-specific differences. In order to address this critical issue, we use a high resolution developing human cerebellum single cell atlas in order to compare to extended bulk and single cell transcriptomes profiles from pediatric solid tumors. In result, we provide novel and confirmatory findings for the cellular association of medulloblastoma SHH, Group3 and Group4 as well as pilocytic astrocytoma, using comprehensive approaches to decipher the cellular composition and map the origins of childhood brain tumors. We also shed light on the cellular origins of posterior fossa ependymoma and radiation-induced glioma (secondary tumor, occurring after medulloblastoma). As a common feature among the tumor similarity to normal cell types, we identify gradients of differentiation, starting from early progenitor cells to more differentiated cell states, observed in all cerebellar tumor entities investigated at single cell level; thus reflecting possible lineages of origin. Pertaining to clinical application, we identified specific developmental genes shared between cerebellar lineages and associated tumors, and tumor-specific genes absent in all cerebellar lineages. These two categories of genes comprise candidate lineage markers for faithful modeling and, if absent from other organ systems after birth, could become an important source of potential therapeutic targets. Importantly, all analysis results are publicly available via an interactive online user interface (brain-match.org) that serves as an open valuable resource for the scientific community.
Changing patterns of second primary malignancies and cause-specific mortality among patients with major salivary glands cancers in the United States: A population-based study.
Authors: Karthik Chamarti, Bibek Bakhati, Vasudha Rudraraju, Maneesh Mannem, Maryam Rajput, John Garza, Kelash Bajaj
Journal: Journal of Clinical Oncology (2022)

e18081 Background: Salivary gland neoplasms are rare entities that comprise approximately 5% of all head and neck malignancies. The incidence of major salivary gland (MSG) cancers has increased about 54% from 1970 to 2000 in the United States (US). We undertook this study to investigate the risk of second primary malignancies (SPMs) and cause-specific mortality (CSM) in patients with MSG cancers using a national registry from the US. Methods: We estimated the incidence of SPMs among two-month survivors of MSG cancers using the Surveillance, Epidemiology, and End Results (SEER)-18 registries between 2008 to 2018. The risk of SPMs were calculated using standardized incidence ratios (SIRs) and the CSM by standardized mortality ratios (SMRs) and absolute excess risk (AER)/10,000 population. Results: We included 845 patients with MSG cancers in this study. The median age of diagnosis was 67 yrs (range 0 - 85 yrs). The median follow-up duration was 24 months (range 0 - 130 months). The median latency period for SPM development was 30 months (range 4 - 117 months). A total of 38 (4.5%) patients developed 41 SPMs at last follow-up. The SPM risk for cohort was significantly elevated (SIR = 1.81, 95% confidence interval [CI] = 1.30 - 2.46) compared with general population. The SPM risk was statistically higher among males (SIR = 2.42, 95% CI = 1.66 - 3.42) but not significant in females (SIR = 0.95, 95% CI = 0.44 - 1.81). Specific sites with highest SPMs risk included tonsil (SIR = 52.45, 95% CI = 1.33 - 292.22) followed by oral cavity (SIR = 15.55, 95% CI = 7.11 - 29.52). The risk for tonsil cancers were high from 5 to 10 years of initial diagnosis. While risk for oral cavity cancers, remained high throughout follow-up period. At the last follow-up, 214 (25%) patients had died. There was statistically significant risk of mortality due to MSG cancers (SMR = 5,453.61, 95% CI = 4,385.34 - 6,703.41, AER = 517.87) and oral cavity cancers (SMR = 663.40, 95% CI = 537.97 - 809.29, AER = 557.41) (Table). Conclusions: Our study concludes that men with MSG cancers are at an increased risk for SPMs compared to women. The risk of specific SPMs (tonsil and oral cavity cancers) was high even after a long period from the initial diagnosis of MSG cancers. This highlights the need for long-term surveillance in these patients for SPMs development.[Table: see text]
Sex-related differential susceptibility to ponatinib-induced cardiotoxicity and its relationship to modulation of Notch signaling in a murine model
Authors: R Madonna, DP Pieragostino, DP Pieragostino, MC Cufaro, MC Cufaro, PD Del Boccio, PD Del Boccio, AP Pucci, AP Pucci, LM Mattii, LM Mattii, VD Doria, VD Doria, CD Cadeddu Dessalvi, CD Cadeddu Dessalvi, RZ Zucchi, RZ Zucchi, GM Mercuro, GM Mercuro, RD De Caterina, RD De Caterina
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukemia, has proven cardiovascular toxicity. Although sex is a risk factor for PON-induced cardiotoxicity in humans, little is known about its mechanisms in general, and sex-related mechanisms in particular. Objectives To determine the mechanisms of sex-related PON-induced cardiotoxicity and identify potential rescue strategies in a murine model. Methods 24-months-old male and female C57B5 mice were treated with 3 mg/kg/day of PON or vehicle via oral gavage for 28 days, with/without siRNA-Notch1 or siRNA-scrambled via tail vein every 3 days. Results PON + scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells, a higher percentage of senescence-associated β-galactosidase positive senescent cardiac areas, as well as a lower reactivity degree for the survival marker Bmi1 than female counterparts. Proteomics analysis of cardiac tissue showed upstream activation of nitric oxide synthase (NOS) type 2, downstream activation of cell death and production of reactive oxygen species in PON + scrambled siRNA- compared to vehicle or PON + Notch1 siRNA-treated male mice. Upstream analysis showed beta-estradiol activation, while downstream analysis showed activation of cell survival and inhibition of cell death in PON + scrambled siRNA compared to vehicle-treated female mice. PON + scrambled siRNA-treated mice also showed a downregulation of cardiac actin, which was more marked in male; as well as vessel density, which was more marked in female mice. Female hearts showed a greater extent of cardiac fibrosis than male counterparts at baseline, with no significant changes after PON treatment. In contrast, PON + scrambled siRNA-treated mice had less fibrosis than vehicle or PON + Notch1-siRNA-treated mice. Left ventricular systolic dysfunction shown in PON + scrambled siRNA-treated male mice and - to a lesser extent - by female mice was similarly reversed in both PON + Notch1-siRNA-treated male and female mice (Table 1). Conclusions We found a sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can improve our understanding of sex-related differences and help identify biomarkers in PON cardiotoxicity.
Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, <i>EGFR</i>-mutated non-small cell lung cancer (NSCLC).
Authors: Jonathan W. Goldman, Hidehito Horinouchi, Byoung Chul Cho, Pascale Tomasini, Martin Dunbar, David Hoffman, Apurvasena Parikh, Vincent Blot, D. Ross Camidge
Journal: Journal of Clinical Oncology (2022)

9013 Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for &gt; 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (&gt; 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]
Reexamining Medicaid Patient Review and Restriction Programs Amid the Evolving Opioid Epidemic
Authors: Michael A. Incze, A. Taylor Kelley, Kimberly Johnson
Journal: JAMA Internal Medicine (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
An update to a retrospective comparison of results between the National Breast and Cervical Cancer Early Detection Program and NCI cancer center based early detection program with evidenced based patient navigation and social work support.
Authors: Celeste Vaughan-Briggs, Edith P. Mitchell, Vincent Pepe
Journal: Journal of Clinical Oncology (2022)

e18572 Background: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) through the CDC has provided uninsured women access to breast and cervical cancer screening/diagnostic services. The uninsured face obstacles which include fear, lack of access and trust in the system, financial and logistical barriers to accessing health care services (Natale-Pereira, et.al, 2011) Disparities in access to screening and diagnostic testing, cancer treatment and survivorship is well documented for medically vulnerable populations that impact stage of diagnosis and mortality (Guadagnolo, Dohan &amp; Raich 2011). The Jefferson's program participates in the NBCCEDP program and uses other private resources which incorporate Social Work core competencies that provide assistance to address barriers. The program navigates along the continuum of cancer care (e.g, prevention, screening, treatment and survival). We have found in a comparative analysis that TJUH’s program has higher rates of diverse racial and ethnic participation of key medically underserved demographics than the National Program. Methods: TJUH's program employs a clinical model, Clinical Patient Navigation with a Licensed Clinical Social Worker operating from a strengths based framework to direct care with administrative support. The program utilizes best practices for working with the at risk population: translation services for the Limited English Proficient, appointment confirmation, transportation assistance and psychosocial support from initial point of contact through final diagnosis. Program staff coordinate internal and external referrals from multiple providers. Results: The study population includes 3144 participants who received breast and cervical cancer screening services through the program from 2012 through 2020. 13.9% were white, 41.7% were African-American, 24.5% were Asian and 19.1% Latinx participated in the program, Table. The age of the participants was slightly younger than the National program as well with 15% under 40, 46% between the ages of 40-49. Conclusions: TJUH’s program provides comprehensive psychosocial support to address barriers along the continuum of screening and diagnostic services leading with increased participation among at risk populations. This further reduces no show rates and participants being lost to follow up. TJUH’s program screens a larger proportion of African American and Asian and younger women compared to the NBCCED program. Additionally, we serviced a slightly younger population than the national program. TJUH’s program addresses health disparities and inequity in access to cancer screening services as shown by the data of the diversity of the participants.
Neoadjuvant nivolumab in early-stage non–small cell lung cancer (NSCLC): Five-year outcomes.
Authors: Samuel Rosner, Joshua E. Reuss, Marianna Zahurak, Janis M. Taube, Stephen Broderick, David Randolph Jones, Jamie E. Chaft, Patrick M. Forde
Journal: Journal of Clinical Oncology (2022)

8537 Background: Neoadjuvant (neoadj) immune checkpoint blockade (ICB) with anti-PD-1 therapy has shown increasing promise for early stage NSCLC, with long-term clinical outcomes still maturing. Our group reported the first phase I/II trial of neoadj nivolumab (nivo) in resectable NSCLC, finding therapy to be safe and feasible. We now present final clinical results from this cohort, representing the longest follow up data for neoadj anti-PD-1 to date. Methods: Two doses of neoadj nivo (3 mg/kg) were given prior to resection in 21 patients (pts) with resectable NSCLC. 5-year (yr) follow-up data, including recurrence-free survival (RFS), overall survival (OS) and association with pathologic response were tabulated. Event time distributions were estimated with the Kaplan-Meier method. All p-values are two-sided with 0.05 significance level. Results: At a median follow up of 63 months, 3-, 4- and 5-yr survival rates were 85, 80, and 80% respectively. RFS rates at 3-, 4- and 5-yrs were 65, 60, and 60% respectively. As previously reported, major pathologic response (MPR: ≤10% viable tumor) was 45%, and pathologic complete response (pCR) rate was 10%. The hazard ratio (HR) for pathologic down-staging was in the direction of improved RFS, without meeting statistical significance (HR 0.36, 95% CI 0.07-1.75, p = 0.2). RFS HR estimates for MPR and an alternative pathologic cut-off of less than 50% residual tumor (RT), were 0.61, (95% CI 0.15-2.44, p = 0.48) and 0.36, (95% CI 0.09-1.51, p = 0.16) respectively. The direction of the effect of pre-treatment PD-L1 positivity (≥1%) was to improve RFS (HR 0.36, 95% CI 0.07-1.85, p = 0.22). At 5-yr follow up, 8 of 9 (89%) pts with MPR were alive and no cancer deaths have occurred. Amongst pts with MPR, 1/9 pts had a cancer recurrence in the mediastinum treated successfully with definitive chemoradiotherapy. Both pts with pCR are alive and without recurrence. Patterns of all recurrences in this cohort are summarized in table 1. No long-term immune-related adverse events have occurred other than one G3 dermatologic event. Conclusions: The 5-yr clinical outcomes for neoadj nivo in resectable NSCLC compare favorably to historical trends. MPR trended toward improved RFS, while definitive conclusions are limited by our cohort size and overall low recurrence rate. Thresholds of %RT beyond pCR and MPR in this setting should be explored in larger prospective studies. PD-L1 expression may play a role in predicting long-term response, but larger prospective studies are needed. Clinical trial information: NCT02259621. [Table: see text]
Epigenetic Regulation to Enhance Graft-versus-Leukemia Activity
Authors: Natalie Köhler, Robert Zeiser
Journal: Cancer Discovery (2022)

Accumulating evidence supports that loss of HLA expression contributes to relapse after allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanisms behind this evasion strategy are unclear. The groups of Luca Vago and Raffaella Di Micco identified the polycomb repressive complex 2 (PRC2) as a key epigenetic driver of immune escape after allo-HCT by reducing the chromatin accessibility of HLA class II molecules, which could be targeted by pharmacologic inhibition of PRC2 subunits. See related article by Gambacorta et al., p. 1449 (10).
GCT-04. Pattern of Treatment Failures in Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT): A Pooled Analysis of Clinical Trials
Authors: Adriana Fonseca, Cecile Faure-Conter, Matthew Murray, Jason Fangusaro, Shivani Bailey, Stewart Goldman, Soumen Khatua, Didier Frapaz, Gabriele Calaminus, Girish Dhall, James Nicholson, Eric Bouffet, Ute Bartels
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.
PSMA PET disease extent for European Association of Urology biochemical recurrence risk groups: An international multicentre study
Authors: W. Fendler, J. Ferdinandus, A. Farolfi, S. Washington, O. Mohamad, M. Pampaloni, P. Scott, M. Rodnick, B. Viglianti, M. Eiber, K. Herrmann, J. Czernin, W. Armstrong, J. Calais, T. Hope, M. Piert
Journal: European Urology (2022)
Diagnosis of prostate cancer in men treated with 5-alpha-reducates inhibitors with multi-parametric MRI: Results of a multicenter international collaboration
Authors: U.G. Falagario, A. Lantz, I. Jambor, G.M. Busetto, L. Carmignani, E. Montanari, P. Bove, P. Gontero, A. Sciarra, P. Di Tonno, C. Trombetta, P. Bassi, G. Simone, V. Mirone, A. Antonelli, L. Schips, P. Bostrom, F. Porpiglia, T. Nordström, O. De Cobelli, L. Cormio, G. Carrieri, M. Ferro
Journal: European Urology (2022)